Coronary artery disease (CAD) remains the leading cause of death in the West, in part because of the still limited options for the treatment of diffuse CAD, myocardial infarction and congestive heart failure (Lloyd-Jones et al., Circulation, 119(3): 480-486 (2009); Taylor et al., J. Heart Lung Transplant, 23(7): 796-803 (2004); Lietz et al., Circulation, 116(5): 497-505 (2007); Anyanwu et al., Brit. Med. J., 326(7388): 509-510 (2003)). Cardiac stem cell therapy has been embraced as a new approach to treating end-stage heart disease that theoretically repopulates otherwise permanently scarred myocardium with contractile cells (Leor et al., Circulation, 94(Suppl. 9): II332-II336 (1996); Taylor et al., Nature Med., 4(8): 929-933 (1998); Tomita et al., Circulation, 100(Suppl. 19): II247-II256 (1999); Orlic et al., Nature, 410(6829): 701-704 (Apr. 5, 2001); Scorsin et al., J. Thorac. Cardiovasc. Surg., 119(6): 1169-1175 (2000); Hare et al., Curr. Opin. Organ Transplant, 13(5): 536-542 (2008); Rosenzweig, N. Engl. J. Med., 355(12): 1274-1277 (2006); Murry et al., J. Am. Coll. Cardiol., 47(19): 1777-85 (2006); Menasche, J. Mol. Cell. Cardiol., 50(2): 258-265 (2010)). The creation of induced pluripotent stem cells (iPSCs) and the generation of cardiomyocyte-like cells from iPSCs appear to have represented breakthroughs in this field (Min et al., J. Appl. Phys., 92(1): 288-296 (2002); Takahashi et al., Cell, 131(5): 861-872 (2007); Yu et al., Science, 318(5858): 1917-1920 (2007); Okita et al., Nature, 448(7151): 313-317 (2007); Xu et al., Proc. Natl. Acad. Sci. (USA), 106(3): 808-813 (2009); Gai et al., Cell Biol. Intl., 33(11): 1184-1193 (2009); Mauritz et al., Circulation, 118(5): 507-517 (2008); Nelson et al., Circulation, 120(5): 408-416 (2009); Narazaki et al., Circulation, 118(5): 498-506 (2008); Zhang et al., Circ Res., 104(4): e30-e41 (2009)), but recent reports of iPSC tumorogenicity and immunogenicity may ultimately reflect limits to the clinical applicability of iPSCs, as may the logistic challenges of iPSC delivery in the clinical setting (Okita et al., Circ Res., 109(7): 720-721 (2011); Apostolou et al., Nature, 474(7350): 165 (2011); Mummery, N. Engl. J. Med., 364(22): 2160-2162 (2011); Zhao et al., Nature, 474(7350): 212-214 (2011)).
The recent discovery that a trio of cardio-differentiating transcription factors could be used to generate induced cardiomyocytes (iCM) directly from somatic cells (Ieda et al., Cell, 142(3): 375-386 (2010)) offers the exciting new possibility of generating autologous cells that possess characteristics that are at least consistent with that of a cardiomyocyte phenotype (Ieda et al., Cell, 142(3): 375-386 (2010); Efe et al., Nature Cell. Bio., 13(3): 215-222 (2011); Qian et al., Nature, 485(7400): 593-598 (2012); Passier et al., Cell Stem Cell, 7(2): 139-141 (2010); Song et al., Nature, 485(7400): 599-604 (2012); Srivastava et al., Circ. Res., 111(1): 5-8 (2012); Jayawardena et al., Circ. Res., 110(11): 1465-1473 (2012); Protze et al., J. Mol. Cell. Cardiol., 53(3): 323-332 (2012)). Perhaps more importantly, this novel regenerative strategy offers the intriguing potential to bypass iPSC staging and convert myocardial scar fibroblasts into functional iCM in situ, potentially transforming regions of myocardial infarction back into functioning myocardium (Qian et al., Nature, 485(7400): 593-598 (2012); Song et al., Nature, 485(7400): 599-604 (2012); Srivastava et al., Circ. Res., 111(1): 5-8 (2012); Jayawardena et al., Circ. Res., 110(11): 1465-1473 (2012)). However, recent reports have provided conflicting evidence regarding the potential efficacy of such in situ myocardial regeneration (Qian et al., Nature, 485(7400): 593-598 (2012); Song et al., Nature, 485(7400): 599-604 (2012); Srivastava et al., Circ. Res., 111(1): 5-8 (2012); Jayawardena et al., Circ. Res., 110(11): 1465-1473 (2012); Protze et al., J. Mol. Cell. Cardiol., 53(3): 323-332 (2012); Chen et al., Circ. Res., 111(1): 50-55 (2012)).
Accordingly, there is a need for additional methods for the treatment and understanding of coronary artery disease, including the generation of iCM cells in situ.